Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, understanding how 7TMRs function is an important goal of biological research. We have used receptors for thyrotropin-releasing hormone (TRH) (TRH-Rs), for thyroid-stimulating hormone (TSH-R) and for free fatty acids (GPR40/FFAR1) as model 7TMRs to study their structure and function. During this year, we have studied several new aspects of the structure and function of these receptors. 1) We used newly constructed homology models of TRH-R type 1 (TRH-R1) and TRH-R type 2 (TRH-R2) to further define the structural and functional differences between these two receptors. 2) Using a TRH-R1 homology model, we developed a novel computational approach to discover ligands for this receptor. This approach incorporated the idea that the binding pocket for an unnatural ligand may be different from the pocket for the native ligand. 3) Using homology models, we predicted residues within FFAR1 that are important for agonist recognition and receptor activation, and then showed that these predictions were correct using site-specific mutagenesis. 4) We used our homology model of FFAR1 to perform virtual screening of potential low molecular weight ligands for FFAR1 and discovered novel agonists and antagonists. Based on our research into FFAR1, we were invited to contribute a review article on FFARs.